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PubMed1995

Preservation of cerebral blood flow responses to hypoxia and arterial pressure alterations in hyperammonemic rats.

Acute hyperammonemia causes cerebral edema, elevated intracranial pressure and loss of cerebral blood flow (CBF) responsivity to CO2. Inhibition of glutamine synthetase prevents these abnormalities. If the loss of CO2 responsivity is secondary to the mechanical effects of edema, one would anticipate loss of responsivity to other physiological stimuli, such as hypoxia and changes in mean arterial blood pressure (MABP). To test this possibility, pentobarbital-anesthetized rats were subjected to either hypoxic hypoxia (PaO2 approximately 30 mm Hg), hemorrhagic hypotension (MABP approximately 70 and 50 mm Hg), or phenylephrine-induced hypertension (MABP approximately 125 and 145 mm Hg). CBF was measured with radiolabeled microspheres. Experimental groups received intravenous ammonium acetate (approximately 50 mumol min-1 kg-1) for 6 h to increase plasma ammonia to 500-600 microM. Control groups received sodium acetate plus HCl to prevent metabolic alkalosis. The increase in CBF during 10 min of hypoxia after 6 h of ammonium acetate infusion (84 +/- 19 to 259 +/- 52 ml min-1 100 g-1) was similar to that after sodium acetate infusion (105 +/- 20 to 265 +/- 76 ml min-1 100 g-1). Cortical glutamine concentration was elevated equivalently in hyperammonemic rats subjected to normoxia only or to 10 min of hypoxia. With severe hypotension, CBF was unchanged in both the ammonium (80 +/- 20 to 76 +/- 24 ml min-1 100 g-1) and the sodium (80 +/- 14 to 73 +/- 16 ml min-1 100 g-1) acetate groups. With moderate hypertension, CBF was unchanged. With the most severe hypertension, significant increases in CBF occurred in both groups, but there was no difference between groups. We conclude that hypoxic and autoregulatory responses are intact during acute hyperammonemia. The previously observed loss of CO2 responsivity is not the result of a generalized vasoparalysis to all physiological stimuli.

Ammonia↗

PubMed1988

Effect of valproate on renal metabolism in the intact dog.

Valproate is an antiepileptic drug known to induce hyperammonemia in humans. This hyperammonemia might result from a reduced detoxification of ammonium in the liver and/or from an accelerated renal ammoniagenesis. Six dogs with normal acid-base equilibrium and eight dogs with chronic metabolic acidosis were infused with valproate directly into their left renal artery in order to obtain arterial concentrations around 3 to 4 mM. The arterial ammonium concentration rose only in chronically acidotic dogs, whereas the lactate concentration and the lactate/pyruvate ratio increased in both groups. The urinary excretion of lactate and pyruvate increased markedly but the urinary excretion of other relevant metabolites remained minimal. Renal glutamine utilization and ammonium production were not changed by valproate administration in normal dogs but increased modestly in acidotic dogs. However, renal lactate utilization was drastically reduced and in fact, changed into a net production of lactate. Valproate strikingly reduced the renal cortical concentrations of glutamine, glutamate, alphaketoglutarate and citrate, and more modestly those of malate, oxaloacetate, aspartate, alanine and ATP. By contrast, the tissue lactate concentration and the lactate/pyruvate ratio were markedly increased. In experiments with brush border membrane vesicles, valproate inhibited the lactate transporter. These results suggest that high concentrations of valproate drastically inhibited the proximal reabsorption and the proximal and distal oxidation of lactate and pyruvate. Valproate probably became itself a significant energetic substrate for the kidney.

Acid-Base Equilibrium↗

PubMed1994

Acute hemodialysis of infants weighing less than five kilograms.

The records of 33 infants weighing 5 kg or less who received acute hemodialysis treatment at Children's Hospital between 1980 and 1991 were reviewed. Dialysis was initiated to treat hyperammonemia (8), primary renal or renovascular disease (7), and acute renal failure (18). The infants weighed 2.2 to 4.0 kg at birth and 27% were born prematurely. The infants were 2 to 120 days of age (median 10 days) and weighed 2.2 to 5.0 kg (median 3.5 kg) at the initiation of hemodialysis. Hemodialysis access was achieved via double-lumen 7 French catheters in 49% of the infants, the ECMO circuit in 24%, and the umbilical vessels in 27%. Thirty-three infants underwent a total of 216 hemodialysis treatments. Only nine treatments were discontinued prematurely: six for intractable hypotension and three for technical problems. Fifty-two percent (17 of 33) of the infants survived through the end of the hemodialysis treatment course. The survival rates for the infants with hyperammonemia (75%) and primary renal disease (71%) were better than those for infants with acute renal failure (33%). The survivors did not differ from those who died with respect to birthweight, weight when hemodialysis was initiated, or the number of hemodialysis treatments administered. We conclude that infants weighing less than 5 kg can be treated successfully with hemodialysis. Patient survival is related to underlying medical problems, not to complications of hemodialysis.

Acute Kidney Injury↗

PubMed1975

Treatment of carbamyl phosphate synthetase deficiency with keto analogues of essential amino acids.

Congenital carbamyl phosphate synthetase deficiency was diagnosed by liver biopsy in a 13-year-old girl, alpha-Keto analogues of essential amino acids have been shown to spare nitrogen by reducing urea formation; hence, they were given to this patient in the hope of reducing hyperammonemia and improving protein tolerance. After intravenous infusion of the keto analogues of valine, leucine, isoleucine, methionine and phenylalanine, the corresponding plasma amino acids, including alloisoleucine and tyrosine, rose sharply. Twenty-four hours later, fasting plasma ammonia had fallen from the preinfusion value of 0.050 to 0.028 mM. Protein intake was kept at 0.5 g per kilogram for two weeks. Addition of keto acids by mouth reduced plasma ammonia and alanine to normal or near normal levels. Seizures and episodes of vomiting and lethargy decreased in frequency. Urinary nitrogen decreased, suggesting that nitrogen balance improved. These data indicate that keto acids may be useful in the treatment of congenital hyperammonemia.

Adolescent↗

PubMed1980

Cerebral dysfunction in asymptomatic carriers of ornithine transcarbamylase deficiency.

We tested the hypothesis that female carriers of ornithine transcarbamylase (OTC) deficiency have cerebral dysfunction as a consequence of episodic hyperammonemia. Seven such carriers were identified by pedigree analysis and protein-tolerance testing. The Wechsler Adult Intelligence Scale was used for evaluation. All IG scores were above 100, but in the protein-tolerant siblings, the full-scale and performance IQ scores were higher by 5.6 and 9.9 points, respectively (P less than 0.02). The absolute difference between the verbal and performance IQ scores was greater in the OTC carriers by 7.8 points (P less than 0.01). This study suggests that clinically asymptomatic carriers of OTC deficiency may have intellectual deficits, perhaps as a result of episodic hyperammonemia.

Amino Acid Metabolism, Inborn Errors↗

PubMed1982

Interactions of aspirin and other potential etiologic factors in an animal model of Reye syndrome.

Recent studies of Reye syndrome (RS) patients have suggested aspirin treatment as a possible factor in the etiology of this often fatal childhood disorder. the relationship of aspirin treatment to other factors that have been strongly implicated (influenza, ammonia toxicity) cannot be examined directly in patients because aspirin treatment is usually initiated by family members in the prodromal period before RS is diagnosed. In this report we describe the use of an animal model for RS in examining the interactions of these several potential etiological factors. Hyperammonemia and coma were produced in young male ferrets by a brief feeding of an arginine-deficient diet. The effects of influenza infection or aspirin treatment (or both) of control and hyperammonemic ferrets on their serum levels of ammonia, glutamic-oxaloacetic transaminase (GOT;L-aspartate:2-oxoglutarate aminotransferase, EC 2.6.1.1), ornithine carbamoyltransferase (OCT; carbamoylphosphate:L-ornithine carbamoyltransferase, EC 2.1.3.3), bilirubin, and salicylate were studied. Liver levels of lipids, proteins, and several urea-cycle enzymes were also determined in the comatose ferrets and compared with those of untreated controls and of controls treated with influenza or aspirin, or both. Synergism of these three factors (hyperammonemia, influenza infection, and aspirin treatment) in causing RS-like alterations in these parameters was observed.

Ammonia↗

PubMed1994

Insulin reverses ammonia-induced anorexia and experimental cancer anorexia.

Previous experiments suggest that experimental cancer-induced anorexia is associated with hyperammonemia and that daily injections of insulin may attenuate the anorexia for several days. In the present study, we determined whether similar daily insulin treatments would correct anorexia induced by the infusion of ammonium salts and compared this feeding response with that of insulin-treated tumor-bearing (TB) rats. Daily treatment of control and anorectic TB rats with systemically administered insulin for six days increased feeding in all control rats and 40% of the TB rats. All insulin-treated groups exhibited equal degrees of hypoglycemia irrespective of anorexia. Basal concentrations of lactate and glucagon were elevated in saline-treated TB rats. Plasma lactate levels were normalized by insulin treatment, whereas glucagon was normalized only in the TB rats that fed to insulin and increased further in TB rats that did not feed to insulin. Elevated hypothalamic tyrosine was reduced in insulin-treated TB rats that ate, and 5-hydroxy-indoleacetic acid was increased further when the rats did not eat. Insulin also blocked anorexia resulting from the intravenous infusion of ammonium salts. Hypothalamic concentrations of tyrosine and tryptophan were increased by the ammonia infusion and reduced significantly in insulin-treated infused rats. These results indicate that insulin treatment can reverse experimental cancer-induced anorexia and hyperammonemia-induced anorexia. Neurochemical changes associated with these treatments are also similar, but not identical.

Ammonia↗

PubMed1989

Nutritional therapy for selected inborn errors of metabolism.

Nutritional approaches are available for the management of several different classes of inborn metabolism errors. In phenylketonuria (PKU), phenylalanine is not properly metabolized; and its accumulation leads to neurologic dysfunction and metal retardation. Altering the diet to limit phenylalanine intake led to remarkable improvement in children with PKU. It was later found that instituting dietary therapy immediately after identification of the disorder in newborns prevented mental retardation. Throughout the 1960s nutritional therapies were found for other inborn disorders, including galactosemia, maple syrup urine disease, and homocystinuria. For the group of disorders associated with defects in the urea cycle, leading to profound hyperammonemia, therapy based on the concept of waste nitrogen excretion (i.e., by increasing excretion of urea cycle intermediates in the urine, nitrogen that would otherwise recycle as ammonia can be eliminated) dramatically produced better control of hyperammonemia and its consequences. Some inborn errors of metabolism respond to vitamin therapy. Biotin-related multiple carboxylase synthetase deficiency can be produced by either of two enzyme defects--holocarboxylase synthetase deficiency or biotinidase deficiency. Both are treatable with biotin supplementation. The symptoms of multiple carboxylase deficiency can also occur after intestinal resection or ingestion of raw eggs. Multiple carboxylase deficiency has been treated successfully in utero by giving the mother biotin supplements. Peroxisomal disorders may respond to dietary management. Liver disease in hereditary tyrosinemia may be accentuated by hypermethioninemia and treated by controlling the blood methionine level. Glycogen storage disease Type I, which causes hypoglycemia, can be controlled by oral administration of cornstarch.

Glycogen Storage Disease Type I↗

PubMed2007

Dysregulation of C/EBPalpha by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. Using two mouse models of HD, we demonstrate that the urea cycle deficiency characterized by hyperammonemia, high blood citrulline and suppression of urea cycle enzymes is a prominent feature of HD. The resultant ammonia toxicity might exacerbate the neurological deficits of HD. Suppression of C/EBPalpha, a crucial transcription factor for the transcription of urea cycle enzymes, appears to mediate the urea cycle deficiency in HD. We found that in the presence of mutant Htt, C/EBPalpha loses its ability to interact with an important cofactor (CREB-binding protein). Moreover, mutant Htt recruited C/EBPalpha into aggregates, as well as suppressed expression of the C/EBPalpha gene. Consumption of protein-restricted diets not only led to the restoration of C/EBPalpha's activity, and repair of the urea cycle deficiency and hyperammonemia, but also ameliorated the formation of Htt aggregates, the motor deterioration, the suppression of striatal brain-derived neurotrophic factor and the normalization of three protein chaperones (Hsp27, Hsp70 and Hsp90). Treatments aimed at repairing the urea cycle deficiency may provide a new strategy for dealing with HD.

Animals↗

PubMed1978

Arginine requirements in immature dogs.

Labrador Retriever puppies (3 kg) were fed L-amino acid (L-AA) diets, containing the equivalent of 14% protein, to determine dietary argnine requirements for optimal growth and maintenance of normal intermediary metabolism. Growth and food consumption were depressed by decreasing the dietary arginine concentration. Urinary citrate and orotate increased with decreasing dietary arginine. Elevated blood orotate, urea and NH4+-N were detected in arginine deficient dogs. More than 0.56% arginine was required to support optimum growth and prevent abnormal loss of urinary metabolites. The effect of dietary nitrogen concentration (14, 21, or 28% L-AA) on arginine requirements was examined in immature Beagles. All arginine deficient dogs and dogs fed the 28% L-AA with arginine showed signs of emesis, excessive salivation and muscle tremors. Hyperammonemia and hyperglycemia were observed 2 hours after force feeding an L-AA diet devoid of arginine. Only hyperammonemia was observed in the Labrador Retrievers fed the same diet but incorporated into a 2% agar gel. Dietary nitrogen concentration or dietary arginine content dit not significantly influence glucose tolerance response to oral glucose loading. These data show that dietary arginine is required in the immature dog and that the requirement is influenced by dietary nitrogen concentration.

Amino Acids↗

PubMed2004

Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism.

Urea cycle disorders (UCD) are human conditions caused by the dysregulation of nitrogen transfer from ammonia nitrogen into urea. The biochemistry and the genetics of these disorders were well elucidated. Earlier diagnosis and improved treatments led to an emerging, longer-lived cohort of patients. The natural history of some of these disorders began to point to pathophysiological processes that may be unrelated to the primary cause of acute morbidity and mortality, i.e., hyperammonemia. Carbamyl phosphate synthetase I single nucleotide polymorphisms may be associated with altered vascular resistance that becomes clinically relevant when specific environmental stressors are present. Patients with argininosuccinic aciduria due to a deficiency of argininosuccinic acid lyase are uniquely prone to chronic hepatitis, potentially leading to cirrhosis. Moreover, our recent observations suggest that there may be an increased prevalence of essential hypertension. In contrast, hyperargininemia found in patients with arginase 1 deficiency is associated with pyramidal tract findings and spasticity, without significant hyperammonemia. An intriguing potential pathophysiological link is the dysregulation of intracellular arginine availability and its potential effect on nitric oxide (NO) metabolism. By combining detailed natural history studies with the development of tissue-specific null mouse models for urea cycle enzymes and measurement of nitrogen flux through the cycle to urea and NO in UCD patients, we may begin to dissect the contribution of different sources of arginine to NO production and the consequences on both rare genetic and common multifactorial diseases.

Animals↗

PubMed2001

Living-related liver transplantation for type II citrullinemia using a graft from heterozygote donor.

BACKGROUND: Type II citrullinemia (CTLN2) characterized by a liver-specific argininosuccinate synthetase deficiency is an adult onset genetical disorder caused by the mutation of SLC25A13 gene, which results in fulminant hyperammonemia often with poor prognosis. METHODS: A 16-year-old Japanese boy presented fulminant hyperammonemia and encephalopathy and recovered after aggressive medical treatment. The patient was diagnosed as CTLN2 by plasma amino acid pattern and detection of the mutated SLC25A13 gene. We performed living-related liver transplantation (LRLT) using a graft from the genetically proven heterozygote father. RESULTS: Serum amino acid concentration was normalized within a day after transplantation without protein restriction and medication. The patient's postoperative course was natural. The patient is back in school 6 months after surgery. CONCLUSIONS: Living-related liver transplantation using a graft from genetically proven heterozygote donors might be a permissible treatment modality for CTLN2. Long-term observation may be necessary to make a definite conclusion possible.

Adolescent↗

PubMed2001

Hyperammonemic coma caused by Providencia rettgeri infection in a child with prune belly syndrome.

OBJECTIVE: To report a case of hyperammonemic encephalopathy in the absence of liver disease caused by a urinary tract infection with a previously unreported organism. DESIGN: Case report. SETTING: Pediatric intensive care unit. Patient: Critically ill child who presented with hyperammonemic coma. INTERVENTION: Bladder drainage and antimicrobial therapy for the urinary tract infection. Measurements: Rapid resolution of the hyperammonemia. MAIN RESULTS: Rapid improvement in the patient's neurologic status and a return to his baseline function without neurologic deficit. CONCLUSIONS: Patients with abnormal urinary collecting systems who present with altered mental status should have a serum ammonia concentration sent as part of the initial evaluation. We have added Providencia species to the list of documented causative organisms in this rare association between urinary tract infections and hyperammonemia.

Journal Article↗

PubMed2006

Evaluation and management of patients with propionic acidemia undergoing liver transplantation: a comprehensive review.

Propionic acidemia is a rare metabolic disorder that often results in episodic hyperammonemia, basal ganglia infarction, mental retardation, and cardiomyopathy. OLT has been used as a treatment for propionic acidemia, but its benefit in patients with this disease is unclear. The current study was undertaken to clarify the role of OLT in the management of this disease. The medical literature, a national registry of US OLT recipients, and a single institution liver transplant experience were reviewed for cases of OLT for propionic acidemia. Accumulated cases demonstrate that OLT has resulted in clear evidence of clinical improvement in several patients, often obviating the need for dietary restriction or other forms of medical management. OLT appears to halt the decline in neurocognitive function often associated with propionic acidemia. In total, 12 patients with propionic acidemia have undergone a total of 14 OLTs. A quantitative analysis of outcomes shows an overall patient survival rate of 72.2% at one year after OLT. In conclusion, OLT should be considered a treatment option for patients with propionic acidemia who continue to experience episodes of hyperammonemia in spite of maximal medical therapy. Early OLT may limit the development of mental retardation and/or cardiomyopathy.

Adult↗

PubMed1989

Methylsuccinate and mesaconate in urine of patients treated with sodium benzoate.

Two unusual peaks were found on gas chromatography of urine from four hyperammonemic patients treated with sodium benzoate. These peaks were identified by gas chromatography/mass spectrometric analyses as methylsuccinate and mesaconate. Of the two unusual substances, methylsuccinate was found to be a contaminant of sodium benzoate administered for the treatment of hyperammonemia. However, mesaconate was not a contaminant of sodium benzoate, though it could be detected in all urine samples from hyperammonemic patients treated with sodium benzoate. Mesaconate can be produced from methylsuccinate in vivo. Considering that mesaconate is an inhibitor of fumarase, the toxic effects of sodium benzoate may be attributable to the mesaconate. It is recommended that methylsuccinate-free sodium benzoate should be used for the treatment of hyperammonemia.

Benzoates↗

PubMed1986

Brain alpha-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution, and effects of inhibitors.

The substrate and cofactor requirements and some kinetic properties of the alpha-ketoglutarate dehydrogenase complex (KGDHC; EC 1.2.4.2, EC 2.3.1.61, and EC 1.6.4.3) in purified rat brain mitochondria were studied. Brain mitochondrial KGDHC showed absolute requirement for alpha-ketoglutarate, CoA and NAD, and only partial requirement for added thiamine pyrophosphate, but no requirement for Mg2+ under the assay conditions employed in this study. The pH optimum was between 7.2 and 7.4, but, at pH values below 7.0 or above 7.8, KGDHC activity decreased markedly. KGDHC activity in various brain regions followed the rank order: cerebral cortex greater than cerebellum greater than or equal to midbrain greater than striatum = hippocampus greater than hypothalamus greater than pons and medulla greater than olfactory bulb. Significant inhibition of brain mitochondrial KGDHC was noted at pathological concentrations of ammonia (0.2-2 mM). However, the purified bovine heart KGDHC and KGDHC activity in isolated rat heart mitochondria were much less sensitive to inhibition. At 5 mM both beta-methylene-D,L-aspartate and D,L-vinylglycine (inhibitors of cerebral glucose oxidation) inhibited the purified heart but not the brain mitochondrial enzyme complex. At approximately 10 microM, calcium slightly stimulated (by 10-15%) the brain mitochondrial KGDHC. At concentrations above 100 microM, calcium (IC50 = 1 mM) inhibited both brain mitochondrial and purified heart KGDHC. The present results suggest that some of the kinetic properties of the rat brain mitochondrial KGDHC differ from those of the purified bovine heart and rat heart mitochondrial enzyme complexes. They also suggest that the inhibition of KGDHC by ammonia and the consequent effect on the citric acid cycle fluxes may be of pathophysiological and/or pathogenetic importance in hyperammonemia and in diseases (e.g., hepatic encephalopathy, inborn errors of urea metabolism, Reye's syndrome) where hyperammonemia is a consistent feature. Brain accumulation of calcium occurs in a number of pathological conditions. Therefore, it is possible that such a calcium accumulation may have a deleterious effect on KGDHC activity.

Ammonia↗

PubMedDate not supplied

Nutritional influence on serum ammonia in young patients receiving sodium valproate.

Hyperammonemia is a common side effect of valproic acid (VPA) therapy. This study was designed to investigate a potential nutritional influence on serum ammonia levels during VPA therapy. In 10 VPA-treated young patients (5 receiving monotherapy, 5 receiving VPA-primidone polytherapy), venous serum ammonia, triglycerides, and cholesterol were measured on 3 consecutive days as follows: (a) after a 13-h overnight fast; (b) 2 h after an oral fat load with butter (1.2 g fat/kg body weight); and (c) 2 h after an oral protein load with fresh cheese (1 g protein/kg body weight). Ten young adults served as controls. After protein load VPA patients had significantly higher serum ammonia levels than controls (mean: 194 vs. 75 micrograms/dl in controls; p less than 0.006). Ammonia values were higher after protein load than after fat load or after fasting (p less than 0.0001). Patients receiving polytherapy had higher ammonia levels than patients receiving monotherapy (not significant). There was no correlation to the height of serum VPA levels. Clinical symptoms attributable to hyperammonemia (vomiting, apathy) were found in only one patient, and her serum ammonia was as high as 426 micrograms/dl. Triglycerides and cholesterol did not show any VPA-induced differences. We assume that VPA alters the short-term regulation of ureasynthesis. We recommend the avoidance of high protein intake in patients receiving VPA therapy, especially in young patients receiving polytherapy or comedication, or in risk situations like serious infections.

Adult↗

PubMed1993

Effects of L and D-carnitine on brain energy metabolites in mice given sublethal doses of ammonium acetate.

Previous studies in our laboratory have shown that L-carnitine suppresses seizures and alterations of brain energy metabolism in mice caused by hyperammonemia. The present study was done to exclude the effects of seizures on brain energy metabolism. When sublethal dose of ammonium acetate (12 mmol/kg b.wt.) was injected to mice, all mice survived without developing seizures, while clear increase of brain ammonia and alterations of brain energy metabolites were seen. In L-carnitine-treated animals, the levels of ammonia, AMP and lactate were lower and those of ATP and phosphocreatine were higher than in untreated animals. Treatment with D-carnitine also preserved the phosphocreatine level. This indicates that the improvement of brain energy metabolism by L-carnitine in hyperammonemia is not simply a result of the suppression of seizures, and that the "physiological" function of carnitine may not be the sole mechanism underlying this effect.

Acetates↗